Abstract Significance: Chronic pain is a significant public health problem associated with tremendous personal and economic burden. First-line treatment consists of opioid medications yet, despite only moderate efficacy and unpleasant side effects, rates of opioid prescriptions have quadrupled over the past 15 years. Related to this increase are unacceptably high rates of misuse, overdose and mortality which have led to an opioid crisis. Non- opioid strategies for treating pain are needed. Compounds that can be combined with and enhance analgesic effects of lower-dose opioids without increasing rewarding properties of either drug are referred to as ?opioid- sparing? medications. Premise: Preclinical data indicate cannabinoids enhance antinociceptive effects of opioids; results from human studies are mixed. In addition, CB1 agonists increase opioid rewarding effects, which limits their utility as opioid-sparing medications. Cannabidiol (CBD) is a non-psychoactive endocannabinoid modulator that potentiated morphine antinociception in an animal model without increasing morphine's rewarding properties. Its ability to alter morphine analgesia in humans has not yet been studied. Approach: We propose a double-blind, placebo-controlled, within-subject randomized crossover (3- session) study of 28 healthy males and females who report exposure to cigarettes or marijuana (smoked route) and at least 3 lifetime episodes of opioid use but currently are not using opioids. Each participant will receive oral morphine (0, 15, and 30 mg; 1 dose/session) followed by CBD (puffs from 0, 3.4 and 12.7% cigarettes; 3 ascending doses/session). At each CBD cumulative dose (within-session) in combination with morphine (between-session), we will assess heat, cold and pressure pain sensitivity, reinforcing, subjective and physiological effects. Specific aims are to determine whether: (1a) morphine alone dose-dependently increases heat and pressure pain threshold and tolerance; decreases respiration; and increases drug liking and economic demand; (1b) CBD alone dose-dependently decreases pain sensitivity without affecting respiration or abuse potential; and whether CBD dose-dependently (2a) increases morphine antinociception, without worsening (2b) physiological or safety/tolerability parameters or (2c) morphine's abuse liability, relative to placebo CBD/morphine. This innovative project will develop a rigorous human laboratory model for testing non-opioids that might directly reduce pain sensitivity and/or augment opioid analgesia without enhancing their rewarding effects. Long-range goals are to efficiently develop and evaluate novel compounds with opioid- sparing effects that can be safely co-administered with opioids, thus enabling use of lower-dose opioids for safer, effective pain relief, with fewer side effects and reduced risk of overdose and mortality. This is the first known study to investigate the ability of CBD to alter morphine's analgesic effects in humans. If successful, the model will have a lasting impact on developing and testing medications for mitigating reliance on chronic use of opioid medications for pain relief. Thus, the proposed work has exceptional potential to improve scientific knowledge and clinical care.